Butyrate (BU), a gut microbiota-derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular mechanism of BU has not been fully interpreted. This work aimed to verify the protective effects of BU against MPTP/MPP -induced neurotoxicity and explore the mechanisms involved. The results showed that BU protected against MPTP-induced motor dysfunction and decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels. Additionally, BU pretreatment improved PC12 cell viability and reduced MPP -induced PC12 cell apoptosis. BU treatment also attenuated MPP -stimulated oxidative stress and inflammatory response in PC12 cells. Furthermore, BU inhibited MPTP/MPP -induced hyperactivation of the JAK2/STAT3 signaling in mice and PC12 cells. Besides, a JAK2 agonist, Coumermycin A1 (C-A1), substantially reversed BU-mediated inhibition on JAK2/STAT3 phosphorylation in MPP -challenged PC12 cells and abated BU-induced repression on MPP -triggered apoptosis, oxidative stress, and inflammatory response in PC12 cells. To sum up, BU might exert neuroprotective effects against MPP /MPTP-induced neurotoxicity by inactivating the JAK2/STAT3 signaling.